Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of neurodegeneration with brain iron accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites.

Identification of Autophagy as a Functional Target Suitable for the Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts.

Deterioration of visual quality and acuity as the first sign of ceroid lipofuscinosis type 3 (CLN3), a rare neurometabolic disease.

Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of 'fingerprints' and vacuolized lymphocytes suggest the diagnosis of CLN3.

A novel de novo FEM1C variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs and limb ataxia.

The principal component of the protein homeostasis network is the ubiquitin-proteasome system. Ubiquitination is mediated by an enzymatic cascade involving, i.e.

Desired Characteristics of a Clinical Decision Support System for Early Sepsis Recognition: Interview Study Among Hospital-Based Clinicians.

Background: Sepsis is a major burden for health care systems in the United States, with over 750,000 cases annually and a total cost of approximately US $20 billion. The hallmark of sepsis treatment is early and appropriate initiation of antibiotic therapy. Although sepsis clinical decision support (CDS) systems can provide clinicians with early predictions of suspected sepsis or imminent clinical decline, such systems have not reliably demonstrated improvements in clinical outcomes or care processes.

Development and validation of a prediction model for actionable aspects of frailty in the text of clinicians' encounter notes.

Objective: Frailty is a prevalent risk factor for adverse outcomes among patients with chronic lung disease. However, identifying frail patients who may benefit from interventions is challenging using standard data sources. We therefore sought to identify phrases in clinical notes in the electronic health record (EHR) that describe actionable frailty syndromes.

Elevated Dipeptidyl Peptidase IV (DPP-IV) Activity in Plasma from Patients with Various Lysosomal Diseases.

Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation.

Is there heart disease in cases of neurodegeneration associated with mutations in C19orf12?

Introduction: In mitochondrial membrane protein-associated neurodegeneration (MPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA), patients suffer from optic nerve atrophy and dementia, which are also typical for another group of diseases, the mitochondrial diseases (MD). Around 30% of patients with MD have heart disease, commonly cardiomyopathy and arrhythmias, and 10% experience a major adverse cardiovascular event. The aim of this study was to assess cardiac involvement in MPAN.

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

Objectives: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses.

Methods: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes.

Palliative care in 9 children with neurodegeneration with brain iron accumulation.

Aim: Evaluation of pediatric palliative home care of families with children suffering from neurodegeneration with brain iron accumulation (NBIA) and their parents.

Material And Methods: The children were treated at home by a multidisciplinary team. Densitometry was used to evaluate the condition of the skeletal system.

Brain iron and metabolic abnormalities in C19orf12 mutation carriers: A 7.0 tesla MRI study in mitochondrial membrane protein-associated neurodegeneration.

Background: Mitochondrial membrane protein-associated neurodegeneration is an autosomal-recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia.

Objectives: The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using H MR spectroscopy in clinically manifesting membrane protein-associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers.

Methods: We present data of 4 clinically affected membrane protein-associated neurodegeneration patients (mean age: 21.

Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator deferiprone can reduce brain iron and slow disease progression.

Methods: We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA.

Subthalamic and pallidal oscillatory activity in patients with Neurodegeneration with Brain Iron Accumulation type I (NBIA-I).

Objectives: Neurodegeneration with Brain Iron Accumulation type I (NBIA-I) is a rare hereditary neurodegenerative disorder with pallidal degeneration leading to disabling generalized dystonia and parkinsonism. Pallidal or subthalamic deep brain stimulation can partially alleviate motor symptoms. Disease-specific patterns of abnormally enhanced oscillatory neuronal activity recorded from the basal ganglia have been described in patients with movement disorders undergoing deep brain stimulation (DBS).

Dominant mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.

Background: Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function.

Objectives: To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease.

Methods: Whole exome sequencing was performed in both patients.

Transcranial Sonography in Mitochondrial Membrane Protein-Associated Neurodegeneration.

Introduction: Although the nature of basal ganglia hyperechogenicity in transcranial sonography (TCS) examinations remains unclear, many studies have shown associations between hyperechogenicity and iron accumulation. The role of iron in basal ganglia hyperechogenicity raises interest in the use of TCS in forms of neurodegeneration with brain iron accumulation (NBIA). Here we analyzed TCS and magnetic resonance imaging (MRI) findings among patients affected by one type of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN).

Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12.

Introduction: Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders with accumulation of iron in the brain, mostly basal ganglia. NBIA subtype mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by recently discovered mutations in C19orf12, which encodes a protein localized in the mitochondrial membrane.

Methods: The present and past radiological features of 14 MPAN patients were analyzed.

Retinal and optic nerve abnormalities in neurodegeneration associated with mutations in C19orf12 (MPAN).

Background: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an neurodegeneration with brain iron accumulation (NBIA) subtype with mutation of C19orf12. Optic atrophy is one of the core symptoms in almost all MPAN cases, but the detailed ophthalmologic features of MPAN patients have not yet been described.

Methods: All consecutive symptomatic, gene proven MPAN patients underwent a detailed ophthalmological examination: best corrected visual acuity (BCVA), slit lamp examination, dilated fundus examination, tonometry, optical coherent tomography (OCT) and electrophysiological examinations.

Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions.

The aim of this study was to assess the presence of DYT6 mutations in Polish patients with isolated dystonia and to characterize their phenotype. We sequenced THAP1 exons 1, 2 and 3 including exon-intron boundaries and 5'UTR fragment in 96 non-DYT1 dystonia patients. In four individuals single nucleotide variations were identified.

Long-term outcomes of bilateral pallidal stimulation for primary generalised dystonia.

Objectives: Bilateral pallidal stimulation is an established surgical management for patients with primary generalised dystonia (PGD). The aim of this study was to present our long-term experience of bilateral pallidal stimulation in patients with PGD.

Methods: The study population is composed of 12 patients diagnosed with of PGD (six patients with DYT-1 positive PGD and six patients with DYT-1 negative PGD).